Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), which is more prevalent in women than men (2-3:1). During pregnancy, there is a decrease in the MS relapse rate, most prominent during the third trimester. After parturition, there is often an increase in the relapse rate. Therefore, within a 6 month time frame, there is a profound change in MS disease activity, with both improvement and disease worsening, providing an ideal window of opportunity for study. We are currently working in the area of sex differences in autoimmune disease, focusing on sex differences in susceptibility to experimental autoimmune encephalomyelitis (EAE), a model for MS. As shown in the preliminary results section, we have identified three differing patterns of disease in the B10.PL, SJL and C57BL/6 mouse strains, respectively, and we plan to utilize all three strains to explore the effects of pregnancy on EAE. We have obtained preliminary data showing that immunization of mice during mid-pregnancy or late-pregnancy suppresses the clinical signs of EAE. The goal of this application is to test the hypothesis that disease fluctuation occurring during and soon after pregnancy in MS and EAE are related to changes in the immune response and are influenced by sex and stress steroid hormones. The aims explore the effect of pregnancy on mice with chronic relapsing EAE and the mechanism of that disease modulation. Specifically, the aims are 1) to determine the effect of pregnancy on murine chronic relapsing EAE exploring the effects of pregnancy on three different EAE models differing in genetic background and extent of disease severity, 2) To probe the mechanism of pregnancy effects in EAE by examining the role of cytokine shifts as well as the influences of sex and stress steroid hormones, and 3) To examine the effect of pregnancy on the naive immune system relative to a biased and activated immune response. The long-term goal of this project is to gain a better understanding of the events and mechanisms underlying the pregnancy-induced suppression of EAE and MS.